Normal today, cancer tomorrow

Researchers discover how cancer can develop overnight

By Vanessa Schipani | January 6, 2011

Without warning cancer can arise from a single catastrophic chromosomal event involving tens to hundreds of breaks in the DNA that are haphazardly pieced back together, researchers reported in the January 7th issue of Cell.

Broken chromosomesWikimedia commons/Square87

"In most cancers, a handful of mutations are accumulated over time, gradually evolving into a more aggressive form," said linkurl:Peter Campbell,;http://www.sanger.ac.uk/research/faculty/pcampbell/ blood oncologist at the Wellcome Trust Sanger Institute and lead author of the study. But in some situations, he adds, cancer can come out of nowhere, leaving its victim little time for treatment.
"What is particularly exciting about this observation is that it points to a novel mechanism that affects the stability of the genome in a very localized way," said linkurl:Ronald DePinho,;http://www.hms.harvard.edu/dms/bbs/fac/depinho.html cancer geneticist at the Belfer Institute for Applied Cancer Science at Harvard University, who was not involved in the study. "This paper explains how cancer can form in a relatively short period of time."
Normally when a cell undergoes drastic damage like the shattering of its chromosomes, what researchers call chromothripsis, it dies from a failure to pass innate cell cycle checkpoints that monitor DNA damage during mitosis. Sometimes, however, the cell attempts to rescue itself even after multiple breaks in its double stranded DNA (dsDNA). Though in most cases the repairs probably result in changes that are detrimental to the cells ability to continue dividing, Campbell said, by random chance the hodgepodge of repairs can occasionally amplify cancer genes or delete cancer suppressor genes, instigating the once normal cells to begin dividing uncontrollably.
Campbell and his group used high-throughput sequencing techniques to study the patterns of DNA rearrangements in various cancers -- such as colon, lung, pancreatic, melanoma and bone -- and discovered that massive rearrangements of dsDNA can occur in localized areas, on chromosomes 9 and 13, for example, where important cancer genes are known to exist.
Partly due to the focal nature of the damage, the group argues it's highly unlikely that catastrophic rearrangements occur as separate, sequential events, the traditional view of how cancer forms, but rather as a single, cataclysmic affair. While the phenomenon seems to occur in only a small percentage of all cancers -- just two to three percent --the researchers argue it's actually a substantial amount of cases, given the prevalence of cancer. Furthermore, they estimate that chromosomal breakdowns may account for up to 25 percent of bone cancers.
However, the cause of the damage remains elusive, though "the fact that it occurs more often in bone cancers is a clue about the mechanism of the event," said DePinho. "There must be something fundamentally different about bone cells because they are more susceptible to such catastrophic events."
One possibility, the group speculates, is that the damage occurs as a result of ionizing radiation from sources like x-rays or nuclear disasters, which is known to cause dsDNA breaks. "It's tempting to speculate that the reason we see [the phenomenon] more in bone is because it's more affected by ionizing radiation" than other kinds of cells, said Campbell. "Some radionuclides preferentially home to bone and would therefore preferentially irradiate [it]."
Campbell and his team plan to test this theory by taking tumor samples from people that have been exposed to large amounts of radiation, such as during the Chernobyl nuclear power plant accident in the Ukraine or the atomic bombing of Nagasaki, Japan during World War II. Campbell said they also plan to induce the phenomenon in vitro using lasers, which can have the same localizing effect on DNA as they observed, to see if the massive rearrangements cause the increases in cancer directly.
"Understanding what mechanism is causing these catastrophic events would be an exciting area of future research," said DePinho.
P.J. Stephens et al., "Massive Genomic Rearrangement Acquired in Single Catastrophic Event during Cancer Developement," Cell, 144:27-40, 2011.**__Related stories:__***linkurl:A targeted cancer therapy?;http://www.the-scientist.com/blog/display/57674/ [7th September 2010]*linkurl:Cancer genetics gets personal;http://www.the-scientist.com/blog/display/57150/ [18th February 2010]*linkurl:Cancer genomes sequenced;http://www.the-scientist.com/blog/display/56221/ [16th December 2009]

Comments

Hats off to anyone who can make any generalization about cancer, or the treatment and care of its victims, that holds sway over very many of its variable manifestations. Every significant factor in the development and spread of mutations, and every conceivable variable in interactive behavior between one factor and another. seem only to apply to narrow bands of cell deviations. With our physiology requiring such complex transductions as it does, with one signal sometimes blocking an undesirable event only to triggers another that is undesirable (and vice versa), with apoptosis solving one problem even as it conduces to another, with so much editing required at cell division and during billions of steps in energy conversions, and -- on the higher scale of convergence we call trauma repair and patho-immunology, and with so many occasions of what we would conceive to be only beneficial immunological mechanisms ending up in overkill mode (or inappropriate kill)... the greatest mystery, so far as what issues are in need of being resolved in cancer research, is how any bio-organism manages to maintain itself at all, much less for any extended period of time.\n\nYet, is that really the mystery we need to resolve? Or could we be missing the boat.\n\nOnto that stage -- onto the veritable madhouse scenario in which things go wrong and result in a cascade of unhappy health issues, no matter what we do -- comes researcher after researcher, trying to make sense of some tiny aspect of why some of the dancers on that stage (that is, the stage upon which our physiological components interact) sometimes run head-on into one another, or trip-up one another, or fall off the stage, as it were, and into the orchestra pit.\n\nDo we sometimes tend to seek an untenable goal, in which we hop to preserve an ideal status quo, called "health," mistaking it to be a safe haven, ad place to be desired at all costs, a "correct" homeostatic Shangrala?\n\nIt would be wonderful if we could be certain there is a self-editing "physiological norm," that is "good health." But it could be argued that no such norm -- in a perfect sense -- exists or is possible. This is not to say it has not been a useful myth, to perceive that one is healthy until and unless pushed out of that Utopian state into a "bad" or imperfect one. Many myths are useful, and some may even be "true," but some may be in need of upgrading. Can we examine objectively the pretext that an organism in good health will remain so until and unless deprived of it by some cruel trauma or pathology? Or, could it be that physiological programming, at best, only stacks statistical odds of continuing to live, or continuing to have what we might agree to be quality of life?\n\nCould it be that the mythical physiological state we call "health" (by whatever mechanism or mechanisms we choose to attribute its its evolution to its current state) is but a statistical bias in favor of living for a while longer. but hardly assuring life or quality of life in perpetuity. That seems to be a popular perception. Does its popularity bleed over into research a lot of the time? A preponderance of the time? \n\nThis is not intended to answer a question, but only raise one, this one: While some of us are justified in seeking to understand what is good health, do others of us need to focus on examining what things may be upgradable about it?\n\nPerhaps pitting one bias against the other would promote some higher synthesis than either alone would avail us. \n\nPerhaps some particular pursuits in research should seek to understand how "good health" should be supported and maintained as a status quo beyond need of upgrading, while others should proceed from the point of view of a working hypothesis that our physiological programming is a flawed cacophony in need of -- at the very least -- some creative upgrading in its choreography.\n\nIt goes without saying that some research mixes and mingles these two opposing views. However, it could be argued that the focus of the one conflicts with the focus of the other. \n\nIn closing, let me stipulate that, if this thinking seems to evoke the specter of a philosophical defense of eugenics, that is neither its intent nor a direction toward which it leads. There ways being sought presently, on many research fronts, for circumventing the expressions of otherwise likely genetic pathologies and, hence, upgrading if not unwanted DNA sequences themselves, then at least their consequences. And, for all we know, a day may come when a person's DNA can be rewritten. Hopefully, no one will then object that inducing a DNA, should it be possible, would be tantamount to "playing God," unless, of course, God should be conceived as desiring such patients, by virtue of having received a bad genetic hand are meant to suffer its consequences without mercy. (:>) \n

The hypothesis that, in some instances, cell fragments would so combine as to produce a viable\n"Frankenstein cell," -- one containing unrestrained growth capabilities, or lacking restraint of normal growth-self-regulation capabilities, is indeed one worthy of study.\n\nAllow me to offer that studies of persons exposed to intense radiation, as from the Chernobyl accident, are rampant, and it may be possible to glean from those some statistics on both what rates of cancer, above and beyond the norm, have been found in that population but, also, what kinds. \n\nIt is also worthy of noting that radiation is but one source of chromosomal damage. They can be effected by exposure to certain chemicals, by burns, by electrical current...\n\nIn regard to electrically induced cell damage, Russian researchers, decades ago, when experimenting in search of ways to accelerate healing of broken bones, inserting metal rods into the bone on each side of a break, induced a low voltage electric current and did see bone healing sped up. However, they also saw a significant incidence of cancers developing subsequently in the vicinity of the healing. \n\nWhat would be of especial use, if that research could be replicated, would be what kind of cancers were found. Whether they occurred in skin, connective tissue, bone or other specialized kinds of cells might tie in. \n\nAny other research, in which cancers correlated to the passing of long-sustained electrical current through tissue or bone, might be significant. \n\nIf I recall correctly, the alleged radiomimetic effects of LSD, in breaking chromosomes, may have been exaggerated or misreported in the media. Certain other chemicals (acetone being a remarkable example)are known to damage cells and chromosomes, and to correlate with increased incidences of certain kinds of cancers.\n\nWhat is particularly challenging is the possibility that certain kinds of specialized cells might be more prone -- upon having chromosomes damaged within them -- to having a conglomeration of "Frankenstein" cell fragments combine in a viable way, capable of growth and metastasis.\n\nForgive the "Frankenstein" name, please. Off hand, it seemed apt, for describing something that is knit together from parts of other things, and which might result in the famous line, "It's alive!" No offense is intended by this coinage. \n\nThat term, and these thoughts, are in no way meant to applaud your hypothesis, nor to disparage it. They are offered only by way of sharing thoughts and recollections I had upon reading your article.\n\n